Acute kidney injury (AKI) is a serious disorder that involves a rapid decline in renal function over a period of hours to days. Severe cases can result in end-stage renal disease, and evidence suggests that AKI is a precursor to long-term chronic renal disease (CKD). Despite this, there is no targeted clinical treatment for AKI. Specifically, no therapies exist that accelerate renal recovery or decrease fibrosis and CKD when administered after injury. However, the kidney possesses an inherent capacity to repair after AKI, and a promising approach to ameliorate long-term AKI-mediated damage lies in developing novel therapies that can enhance the natural mechanisms of tissue repair in order to reduce fibrosis and CKD after AKI. Macrophages play a central role in coordinating the injury and repair process after AKI, but the intrinsic mechanisms control macrophage-dependent repair after AKI have been poorly understood. In recent studies we have shown that retinoic acid (RA) signaling plays an important role in regulating this macrophage-dependent repair and fibrosis after AKI and that therapeutic manipulation of this pathway might be used to safely manipulate this RA- dependent response for therapeutic benefit for AKI. In this proposal we plan a series of mouse and cell culture studies to explore the mechanisms by which RA signaling regulates this response, and to develop a novel pre-clinical therapeutic platform to safely and effectively enhance local activation of the RA signaling pathway in the kidney in order to increase macrophage-dependent tissue repair and reduce the likelihood of developing long-term CKD after an episode of AKI.